Cardiovascular risk factors (diabetes, hyperinsutinemia, hypertension, hyperlipidemia), cerebrovascular disease, and Alzheimer's disease (AD) are some of the most common problems in the elderly and represent an important public health burden. These problems often coexist, but it is unclear if the relation between these problems is coincidental or causal. Given the public health importance of cardiovascular and cerebrovascular disease as well as AD, it is important to clarify their relation to one another. We propose to conduct longitudinal and cross-sectional studies of cardiovascular and cerebrovascular disease in relation to AD in the WHICAP II cohort, which began recruitment in 1999 of over 2,000 individuals to complement those still followed from WtllCAP I. We will use data from the baseline examinations in 1999 and from subsequent follow-up assessments. In addition, we propose to conduct a brain imaging in 1,000 individuals without dementia from WHICAP II at the second follow-up assessment that will include quantitative assessment of cerebrovascular disease and of imaging biomarkers of AD, namely hippocampal basal metabolism and hippocampal volumes. We also intend to study the association between the recently discovered haplotype of the phosphodiesterase gene (PDE4D) related to stroke in relation to the outcomes in this project. The assessment of cardiovascular risk factors will include the measurement of hyperinsulinemia, a potentially important risk factor for AD at baseline and the second, third, and fourth follow-ups. The following is a brief description of the aims of this project. AIMI: to conduct longitudinal studies of the associations between cardiovascular risk factors (including insulin and c-peptide) and mild cognitive impairment (MCI), AD, and cognitive decline. AIM 2: to conduct longitudinal studies of the associations between clinical stroke, white matter hyperintensities (WMH) and silent infarcts to MCI, AD, and cognitive decline. AIM 3: to conduct cross-sectional studies of the associations between cardiovascular risk factors and measures of hippocampal volume and basal metabolism. AIM 4: to conduct cross-sectional studies of the associations between clinical stroke, WMH and silent infarcts to imaging measures of hippocampal volume and basal metabolism. AIM 5: to conduct longitudinal studies of the associations between the gene encoding PDE4D and MCI, AD, cognitive decline, and measures of hippocampal volume and metabolism. This proposal provides a unique opportunity to study cardiovascular risk factors and eerebrovascular disease with great detail and in relation to several levels of AD related outcomes: imaging biomarkers, clinical precursors, and changes in specific neuropsychologieal profiles. In addition it is likely to advance the clarification of the mechanisms relating cardiovascular risk factors and cerebrovascular disease to MCI, AD and cognitive decline in the elderly.